GM-CSF induces STAT5 binding at epigenetic regulatory sites within the Csf2 promoter of non-obese diabetic (NOD) mouse myeloid cells.
Myeloid cells from non-obese diabetic (NOD) mouse and human type 1 diabetic (T1D) patients overexpress granulocyte-macrophage colony stimulation factor (GM-CSF). This overproduction prolongs the activation of signal transduction and activator of transcription 5 (STAT5) proteins, involved in GM-CSF-induced control of myeloid cell gene expression. We found that GM-CSF can regulate the binding of STAT5 on the promoter of its own gene, Csf2, within regions previously identified as sites of chromatin epigenetic modification important to the regulation of GM-CSF during myeloid differentiation and inflammation. We found multiple sequence polymorphisms within NOD mouse chromosome 11 Idd4.3 diabetes susceptibility region that alter STAT5 GAS binding sequences within the Csf2 promoter. STAT5 binding at these sites in vivo is increased significantly in GM-CSF-stimulated-bone marrow cells and in unactivated, high GM-CSF-producing macrophages from NOD mice as compared to non-autoimmune C57BL/6 mouse myeloid cells. Thus, GM-CSF overproduction by NOD myeloid cells may be perpetuating a positive epigenetic regulatory feedback on its own gene expression through its induction of STAT5 binding to its promoter. These findings suggest that aberrant STAT5 binding at epigenetic regulatory sites may contribute directly to immunopathology through cytokine-induced gene expression dysregulation that can derail myeloid differentiation and increase inflammatory responsiveness.
Seydel
F
F
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Garrigan
E
E
Stutevoss
B
B
Belkin
N
N
Makadia
B
B
Carter
J
J
Shi
J-D
JD
Davoodi-Semiromi
A
A
McDuffie
M
M
Litherland
S A
SA
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D016415:Sequence Alignment
D002843:Chromatin; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor